Direct Synthesis of Naltrexone by Palladium-Catalyzed N-Demethylation/Acylation of Oxymorphone
dried over Na SO4 and concentrated. The crude material
Soc. Perkin Trans. 1 1994, 911; c) V. Chaudhary, H.
2
was purified by silica gel chromatography (EtOAc/MeOH
Leisch, A. Moudra, B. Allen, V. De Luca, D.P Cox, T.
Hudlicky, Collect. Czech. Chem. Commun. 2009, 74,
1179.
4
:1) to afford naltrexone (7) as a white solid; yield: 0.13 g
(
93%); mp 159–1618C (MeOH), [lit. mp 174–1768C (ace-
[31]
20
tone) ]; R =0.42 (EtOAc/MeOH 4:1); [a] : ꢀ207.00 (c 1,
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f
D
CHCl ); IR (CHCl ): n=3568, 3359, 3010, 2931, 2834, 1723,
3
3
ꢀ
1
1
1
620, 156, 1317, 1146, 1058, 943 cm ; H NMR (600 MHz,
CDCl ): d=6.74 (d, J=8.1 Hz, 1H), 6.60 (d, J=8.1 Hz, 1H),
3
5
3
.82 (bs, 1H, OH), 4.74 (s, 1H), 3.21 (d, J=5.9 Hz, 1H),
.11–3.03 (m, 2H), 2.72 (dd, J=12.0, 4.8 Hz, 1H), 2.58 (dd,
J=18.4, 6.0 Hz, 1H), 2.49–2.39 (m, 3H), 2.34 (ddd, J=14.5,
.0, 3.0 Hz, 1H), 2.18 (ddd, J=12.2, 3.8, 3.8 Hz, 1H), 1.91
m, 1H), 1.66 (ddd, J=14.2, 14.2, 3.3 Hz, 1H), 1.59 (ddd,
J=12.8, 2.7 Hz, 1H), 0.88 (m, 1H), 0.57 (m, 2H), 0.16 (m,
3
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3
2
1
5
H);
C NMR (150 MHz, CDCl ): d=210.02, 142.51,
3
38.80, 129.05, 124.25, 119.90, 117.91, 90.60, 70.32, 62.01,
9.21, 51.07, 43.60, 36.21, 31.36, 30.65, 22.62, 9.42, 4.02, 3.81;
2
4
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Supporting Information
Experimental and spectral data for compounds 7, 11, 12, 13,
4, and 15 are available in the Supporting Information. In
1
2
343; d) W. P. Griffith, B. Reddy, A. G. F. Shoair, M.
addition, details of the optimization of the Pd-catalyzed N-
demethylation as well as alternative suggestions for the
mechanism of intramolecular acyl transfer are included.
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The authors are grateful to the following agencies for finan-
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and Engineering Research Council of Canada (NSERC)
Chem. Soc. Jpn. 2003, 76, 2399.
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2717